The focus of this study is to investigate the role of substrate stiffness in the tissue response to cortical implants in order to create a longer-lasting, more intimate interface with neural tissue. Cortical electrodes have already shown great advances in neuroscience to help understand the structure and function of the brain. Applications to restore motor function to neurologically impaired individuals have shown promise to restore functionality. Cortical electrodes have been unable to achieve the longevity and stability to be employed as a viable clinical option. A constraint on longevity is the formation of a glial scar around an implant. It is proposed that reactions are due to two modes: a macro mode and a micro mode. The macro mode is a shear stress, differential-motion effect caused by a hard implant in soft neural tissue. The micro mode is a mechanotransduction mechanism where cellular pathways activate based on substrate stiffness. The first aim will investigate the cell micro/durotaxis response by using a controllable-stiffness material system to analyze the cellular response via immunohistochemistry (IHC). The second aim will investigate the effect of macro/shear stress by using a mechanically dynamic nanocomposite to gauge tissue response via IHC. The third aim is to assess the tissue response via electrophysiology by using a nanocomposite- encapsulated electrode. Immunohistochemisty of implants and electrophysiology of electrodes will provide quantitative data to differentiate performance of materials. The proposed work is designed to fuse neuroscience and neural engineering viewpoints to merge the fields to understand the fundamentals that will be vital in curing neural disorders and designing future neural devices. The focus of the study is on the cellular response to implant stiffness, and information gained in this study will be broadly applicable to many health arenas. Material stiffness has been implicated in stem cell differentiation, cancer development, spinal cord regrowth, and tissue engineering among other fields. Increasing the longevity of cortical implants will also allow for clinical restoration of function and the investigation of neurological diseases. This study will provide the first comprehensive study of stiffness- based tissue responses to cortical implants in vivo.